The present invention is directed to novel naphthostyrils of formula 
These compounds inhibit cyclin-dependent kinases (CDKs), in particular CDK2. These compounds and their pharmaceutically acceptable salts and esters are anti-proliferative agents useful in the treatment or control of cell proliferative disorders, in particular cancer. The invention is also directed to pharmaceutical compositions containing such compounds, and to methods for the treatment and/or prevention of cancer, particularly in the treatment or control of solid tumors. The compounds of the invention are especially useful in the treatment or control of breast, colon, lung and prostate tumors. The invention is also directed to intermediates useful in the preparation of the above anti-proliferative agents.
Uncontrolled cell proliferation is the hallmark of cancer. Cancerous tumor cells typically have some form of damage to the genes that directly or indirectly regulate the cell-division cycle.
Cyclin-dependent kinases (CDKs) are enzymes which are critical to cell cycle control. See, e.g., Coleman et al., xe2x80x9cChemical Inhibitors of Cyclin-dependent Kinases,xe2x80x9d Annual Reports in Medicinal Chemistry, vol. 32, 1997, pp. 171-179. These enzymes regulate the transitions between the different phases of the cell cycle, such as the progression from the G1 phase to the S phase (the period of active DNA synthesis), or the progression from the G2 phase to the M phase, in which active mitosis and cell-division occurs. See, e.g., the articles on this subject appearing in Science, vol. 274, Dec. 6, 1996, pp. 1643-1677.
CDKs are composed of a catalytic CDK subunit and a regulatory cyclin subunit. The cyclin subunit is the key regulator of CDK activity, with each CDK interacting with a specific subset of cyclins: e.g. cyclin A (CDK1, CDK 2). The different kinase/cyclin pairs regulate progression through specific stages of the cell cycle. See, e.g., Coleman, supra.
Aberrations in the cell cycle control system have been implicated in the uncontrolled growth of cancerous cells. See, e.g., Kamb, xe2x80x9cCell-Cycle Regulators and Cancer,xe2x80x9d Trends in Genetics, vol. 11, 1995, pp. 136-140; and Coleman, supra. In addition, changes in the expression of or in the genes encoding CDK""s or their regulators have been observed in a number of tumors. See, e.g., Webster, xe2x80x9cThe Therapeutic Potential of Targeting the Cell Cycle,xe2x80x9d Exp. Opin. Invest. Drugs, Vol. 7, pp. 865-887 (1998), and references cited therein. Thus, there is an extensive body of literature validating the use of compounds inhibiting CDKs as anti-proliferative therapeutic agents. See, e.g. U.S. Pat. No. 5,621,082 to Xiong et al; EP 0 666 270 A2; WO 97/16447; and the references cited in Coleman, supra, in particular reference no. 10. Thus, it is desirable to identify chemical inhibitors of CDK activity.
It is particularly desirable to identify small molecule compounds that may be readily synthesized and are effective in inhibiting CDK2 or CDK2/cyclin complexes, for treating one or more types of tumors.
4-Alkenyl- and 4-alkynyloxindoles useful in the treatment or control of cancer are disclosed in U.S. Pat. No. 6,130,239. Indolinone (also known as oxindole) compounds asserted to be useful in regulating abnormal cell proliferation through tyrosine kinase inhibition are disclosed in WO 96/40116, WO 98/07695, WO 95/01349, WO 96/32380, WO 96/22976, WO 96/16964 (tyrosine kinase inhibitors), and WO 98/50356 (2-indolinone derivatives as modulators of protein kinase activity). Oxindole derivatives have also been described for various other therapeutic uses: U.S. Pat. No. 5,206,261 (improvement of cerebral function); WO 92/07830 (peptide antagonists); EP 580 502 A1 (antioxidants).
There continues to be a need for easily synthesized, small molecule compounds for the treatment of one or more types of tumors, in particular through regulation of CDKs. It is thus an object of this invention to provide such compounds and compositions containing such compounds.
The present invention relates to naphthostyrils capable of inhibiting the activity of one or more CDKs, in particular CDK2. These compounds are useful for the treatment or control of cancer, in particular solid tumors. In particular this invention is directed to a compound of the formula 
and the pharmaceutically acceptable salts and esters of such compound, wherein R1-R4 are as defined below.
The present invention is also directed to pharmaceutical compositions comprising a pharmaceutically effective amount of any one or more compounds of formula I and a pharmaceutically acceptable carrier or excipient.
The present invention is further directed to a method for treating solid tumors, in particular breast, colon, lung and prostate tumors, by administering to a human patient in need of such therapy an effective amount of a compound of formula I, its salt and/or ester or a combination thereof.
As used herein, the following terms shall have the following definitions.
xe2x80x9cArylxe2x80x9d means an aromatic group having 5 to 10 atoms and consisting of 1 or 2 rings. Examples of aryl groups include phenyl and 1- or 2-naphthyl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic, partially or completely saturated cyclic aliphatic hydrocarbon group containing 3 to 8 atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.
xe2x80x9cEffective Amountxe2x80x9d means an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt or ester thereof, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines, and is thus effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
xe2x80x9cHeteroarylxe2x80x9d groups are aromatic groups having 5 to 10 atoms, one or two rings, and containing one or more hetero atoms. Examples of heteroaryl groups include 2, 3 or 4-pyridyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, pyrrolyl, and imidazolyl.
xe2x80x9cHetero atomxe2x80x9d means an atom selected from N, O and S.
xe2x80x9cHeterocyclexe2x80x9d means a 3- to 10-membered non-aromatic, partially or completely saturated hydrocarbon group, such as tetrahydroquinolyl, which contains one or two rings and at least one hetero atom. Examples of heterocyclic compounds include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, and the like.
xe2x80x9cIC50xe2x80x9d refers to the concentration of a particular naphthostyril required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described in Example 58, infra.
xe2x80x9cLower alkylxe2x80x9d denotes a straight-chain or branched saturated or unsaturated aliphatic hydrocarbon having 1 to 6, preferably 1 to 4, carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, propenyl, propynyl, and the like.
xe2x80x9cPharmaceutically acceptable esterxe2x80x9d refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. Examples of ester groups which are cleaved (in this case hydrolyzed) in vivo to the corresponding carboxylic acids (R24C(xe2x95x90O)OH) are lower alkyl esters which may be substituted with NR25R26 where R25 and R26 are lower alkyl, or where NR25R26 taken together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc.; acyloxyalkyl esters of the formula R24C(xe2x95x90O)OCHR27OC(xe2x95x90O)R28 where R27 is hydrogen or methyl, and R28 is lower alkyl or cycloalkyl; carbonate esters of the formula R24C(xe2x95x90O)OCHR27OC(xe2x95x90O)OR29 where R27 is hydrogen or methyl, and R29 is lower alkyl or cycloalkyl; or aminocarbonylmethyl esters of the formula R24C(xe2x95x90O)OCH2C(xe2x95x90O)NR25R26 where R25 and R26 are hydrogen or lower alkyl, or where NR25R26 taken together form a monocyclic aliphatic heterocycle, such as pyrrolidine, piperidine, morpholine, N-methylpiperazine, etc.
Examples of lower alkyl esters are the methyl, ethyl, and n-propyl esters, and the like. Examples of lower alkyl esters substituted with NR25R26 are the diethylaminoethyl, 2-(4-morpholinyl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl esters, and the like. Examples of acyloxyalkyl esters are the pivaloxymethyl, 1-acetoxyethyl, and acetoxymethyl esters. Examples of carbonate esters are the 1-(ethoxycarbonyloxy)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl esters. Examples of aminocarbonylmethyl esters are the N,N-dimethylcarbamoylmethyl and carbamoylmethyl esters.
Further information concerning examples of and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H. ed. (Elsevier, 1985). See also, H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et. al., Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
xe2x80x9cPharmaceutically acceptable,xe2x80x9d such as pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
xe2x80x9cSubstituted,xe2x80x9d as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
In one embodiment, the invention is directed to a compound of formula: 
or the pharmaceutically acceptable salts or esters thereof, wherein:
R1 is selected from the group consisting of
xe2x80x94H,
xe2x80x94OR5,
halogen,
xe2x80x94CN,
xe2x80x94NO2,
xe2x80x94COR5,
xe2x80x94COOR5,
xe2x80x94CONR5R6,
xe2x80x94NR5R6,
xe2x80x94S(O)nR5,
xe2x80x94S(O)2NR5R6, and
lower alkyl which optionally may be substituted by R7;
R2 is selected from the group consisting of
xe2x80x94H,
xe2x80x94OR5 
halogen,
xe2x80x94CN,
xe2x80x94NO2,
xe2x80x94COOR5,
xe2x80x94CONR5R6,
xe2x80x94NR5R6,
xe2x80x94S(O)nR5,
xe2x80x94S(O)2NR5R6,
lower alkyl which optionally may be substituted by R7, cycloalkyl which optionally may be substituted by R8, and heterocycle which optionally may be substituted by R8;
R3 and R4 are each independently selected from the group of
xe2x80x94H,
xe2x80x94OR5,
xe2x80x94CN,
xe2x80x94NO2,
xe2x80x94COR5,
xe2x80x94COOR5,
xe2x80x94CONR5R6,
xe2x80x94NR5R6,
xe2x80x94S(O)nR5,
xe2x80x94S(O)2NR5R6, and
lower alkyl which optionally may be substituted by R7;
R5 is selected from the group consisting of
xe2x80x94H
lower alkyl which optionally may be substituted by R7,
cycloalkyl which optionally may be substituted by R8,
aryl which optionally may be substituted by R8,
heteroaryl which optionally may be substituted by R8, and
heterocycle which optionally may be substituted by R8;
R6 is selected from the group of
xe2x80x94H
xe2x80x94COR9,
xe2x80x94CONR9R10,
xe2x80x94S(O)nR9,
xe2x80x94S(O)2NR9R10,
lower alkyl which optionally may be substituted by R7, and
cycloalkyl which optionally may be substituted by R8,
or, alternatively, NR5R6 optionally may form a ring having 5-6 atoms, said ring optionally including one or more additional hetero atoms and being optionally substituted by R8;
R7 is selected from the group of
xe2x80x94OR9,
halogen
xe2x80x94CN,
xe2x80x94NO2,
xe2x80x94COR9,
xe2x80x94COOR9,
xe2x80x94CONR9R10,
xe2x80x94NR9R10,
xe2x80x94S(O)nR9,
xe2x80x94S(O)nNR9R10;
R8 is selected from the group of
xe2x80x94OR9,
xe2x80x94CN,
xe2x80x94O,
xe2x80x94NO2,
xe2x80x94COR9,
xe2x80x94COOR9,
xe2x80x94CONR9R10,
xe2x80x94NR9R10,
xe2x80x94S(O)nR9,
xe2x80x94S(O)2NR9R10, and
lower alkyl which optionally may be substituted by R7;
R9 is selected from the group of
xe2x80x94H,
lower alkyl, and
cycloalkyl;
R10 is selected from the group consisting of
xe2x80x94H,
xe2x80x94COR11,
lower alkyl, and
cycloalkyl,
or, alternatively, NR9R10 optionally may form a ring having 5-6 atoms, said ring optionally including one or more additional hetero atoms;
R11 is selected from the group consisting of
lower alkyl, and
cycloalkyl;
a is an optional bond;
n is 0, 1 or 2; and
The letters A, B, C and D in formula I are merely for purposes of identifying each of the different rings in the formula.
In a preferred embodiment of the compounds of formula I, R1 is selected from the group consisting of H, halogen, lower alkyl substituted by halogen, xe2x80x94NO2, xe2x80x94CONR5R6, and xe2x80x94CN. The most preferred lower alkyls substituted by halogen include perfluoroalkyls. Preferred perfluoroalkyls include xe2x80x94CF3. Preferred halogens include F.
In another preferred embodiment of the compounds of formula I, R2 is selected from the group consisting of xe2x80x94H, xe2x80x94OR5, NO2, xe2x80x94CONR5R6, xe2x80x94S(O)nR5, xe2x80x94NR5R6, and lower alkyl which optionally may be substituted by R7. Preferred xe2x80x94OR5 groups include xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94OCH2CH2OH, xe2x80x94OCH2CH2CH2OH, and xe2x80x94OCH2CH2NH2. Preferred lower alkyls include perfluoroalkyl. Preferred perfluoroalkyls include xe2x80x94CF3. Preferred xe2x80x94NR5R6 groups include xe2x80x94NHCH2CH2NH2.
In another preferred embodiment of the compounds of formula I, R3 and R4 are selected from the group consisting of xe2x80x94H and lower alkyl which optionally may be substituted by R7.
In another preferred embodiment of the compounds of formula I, R5 is selected from the group consisting of lower alkyl which optionally may be substituted by R7 and heterocycle which optionally may be substituted by R8.
In another preferred embodiment of the compounds of formula I, R6 is lower alkyl which optionally may be substituted by R7.
In another preferred embodiment of the compounds of formula I, xe2x80x94NR5R6 is a ring having 5-6 atoms, said ring optionally including one or more additional hetero atoms and being optionally substituted by R8.
In another preferred embodiment of the compounds of formula I, R7 is selected from the group consisting of xe2x80x94OR9 and xe2x80x94NR9R10.
In another preferred embodiment of the compounds of formula I, R8 is selected from the group consisting of xe2x80x94OR9 and xe2x80x94NR9R10.
In another preferred embodiment of the compounds of formula I, R9 is selected from the group consisting of H and lower alkyl.
In another preferred embodiment of the compounds of formula I, R10 is selected from the group consisting of H and lower alkyl.
In another preferred embodiment of the compounds of formula I, n is 0.
In another preferred embodiment of the compounds of formula I, xe2x80x9caxe2x80x9d is a bond.
The following are examples of preferred compounds of formula I:
6-Fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one hydrochloride salt,
5-(2-Amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one methanesulfonic acid salt,
5-(2-Amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt,
6-Fluoro-5-methoxy-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-Ethoxy-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(2-hydroxy-ethylamino)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(2-hydroxy-ethoxy)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(3-hydroxy-propoxy)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethoxy)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethoxy)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one methanesulfonic acid salt,
5-(3-Amino-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one acetic acid salt,
5-(2-Amino-2-methyl-propylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-morpholin-4-yl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-piperazin-1-yl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one acetic acid salt,
6-Fluoro-5-methyl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
(rac)-5-sec-Butyl-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-Ethyl-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(2-oxo-imidazolidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
N-[2-[6-Fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylamino]-ethyl]-acetamide,
5-(2-Dimethylamino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt,
5-(2-Diethylamino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-[(R)-3-hydroxy-pyrrolidin-1-yl)]-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(4-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(3-hydroxymethyl-piperidin-1-yl)-3-(1H-pyrrol -2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(3-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(2-hydroxy-ethylsulfanyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(2-hydroxy-ethanesulfinyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
6-Fluoro-5-(2-hydroxy-ethanesulfonyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethylsulfanyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethylsulfanyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one hydrochloride salt,
5-(2-Amino-ethanesulfinyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethanesulfinyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one hydrochloride salt,
5-(2-Amino-ethanesulfonyl)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one,
5-(2-Amino-ethylsulfanyl)-6-fluoro-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one trifluoroacetic acid salt,
6-Fluoro-5-(-(S)-pyrrolidin-2-ylmethylsulfanyl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one, and
6-Fluoro-5-[(S)-(pyrrolidin-3-ylsulfanyl)]-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one.
The compounds disclosed herein and covered by the above formulae may exhibit tautomerism, or structural or stereo isomerism. It is intended that the invention encompasses any tautomeric or structural or stereo isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structural or stereo isomeric form utilized within the formulae drawn above.
The compounds of the invention may be prepared by processes known in the art. Suitable processes for synthesizing these compounds are provided in the examples. Generally, compounds of formula I may be prepared according to one of the below described synthetic routes. 
Where PG is a suitable protecting group such as tert-butoxycarbonyl. 
Where xe2x80x9cdeprotectionxe2x80x9d means using suitable methods well known in the art of chemical synthesis to remove protecting groups, such as treating with acid to remove the tert-butoxycarbonyl group. 
Preferred base includes 1 N sodium hydroxide, which upon heating in the presence of compound VI yields compound VII, and on prolonged heating, yields compound I. 
Preferred base includes NaH. 
Formation of compound I can be achieved by using organo-cuprate reagents. 
Formation of compound I can be achieved by using organo-zinc/copper reagents where X is Br or I.
Compounds of Formula I can also be obtained by chemical modification of another compound of Formula I using chemical transformations well know in the art.
In an alternative embodiment, the present invention is directed to pharmaceutical compositions comprising at least one compound of formula I and/or a pharmaceutically acceptable salt or ester thereof.
These pharmaceutical compositions can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard or soft gelatin capsules, solutions, emulsions or suspensions. They can also be administered rectally, for example, in the form of suppositories, or parenterally, for example, in the form of injection solutions.
The pharmaceutical compositions of the present invention comprising a compound of formula I and/or the salt or ester thereof, may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, dragee-making, or lyophilizing processes. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, steric acid or its salts can be used as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules include vegetable oils, waxes and fats. Depending on the nature of the active substance, no carriers are generally required in the case of soft gelatin capsules. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oils, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semi-liquid polyols.
The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances, including additional active ingredients other than those of formula I.
As mentioned above, the compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds are particularly useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
In another embodiment, the present invention is also directed to novel intermediates useful in the preparation of compounds of formula I. These novel intermediates include the following compounds:
2-(1-Hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester,
2-tert-Butoxycarbonyloxy-5-fluoro-4-iodo-indole-1-carboxylic acid tert-butyl ester,
2-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester,
2-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-4-indole-1-carboxylic acid tert-butyl ester,
5-Fluoro-4-[3-oxo-3-(1H-pyrrol-2-yl)-propyl]-1,3-dihydro-indol-2-one,
(Z)-5-Fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one,
[2-[6-Fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-yloxy]-ethyl]-carbamic acid tert-butyl ester,
[2-[6-Fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester,
3,4-Dimethyl-2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester,
2-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester,
2-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-3,4-dimethyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester,
5-Fluoro-4-[1-iodo-3-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one,
[2-[6-Fluoro-2-oxo-3-(3,4-dimethyl-1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-ethyl]-carbamic acid tert-butyl ester,
5-Fluoro-4-[3-oxo-3-(1H-pyrrol-2-yl)-propyl]-1,3-dihydro-indol-2-one,
(xc2x1)-trans-Thioacetic acid-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyl] ester,
(xc2x1)-5-[trans-3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentylsulfanyl]-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one, and
(S)-3-[6-Fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylsulfanyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.